Analysis of proteasome stress in different cell types defines a conserved transcriptional response signature and its modulation with aging.

The proteasome is essential for proteostasis. Transcriptional induction of proteasomal components occurs when the proteasome is inhibited, but an overview of the transcriptional responses caused by proteasome perturbation is missing. Here, we profiled transcriptional changes caused by chemical and genetic proteasome inhibition and defined time-dose responses in cells and organoids. Induction of proteasome components varied by cell type and inhibition mode, whereas other responses were consistent, including upregulation of chaperones and secreted factors, and repression of cell cycle regulators. A proteasome stress response signature was defined based on the genes consistently modulated across systems, and applying this signature to aging datasets revealed activation of this stress response in some tissues, including skeletal muscle. Moreover, secreted factors within the signature showed similar age-related changes in human plasma, suggesting systemic activation of this stress response with aging. Together, these findings define a transcriptional signature for monitoring proteasome stress during aging and age-related diseases.